The long-range goal of this laboratory is to elucidate the role of mammalian mitochondrial gene products in cellular energy metabolism, organelle biogenesis, and intermediary metabolism. These areas impact human health at several levels including. genetic diseases, developmental biology, and cancer. At present, a major portion of our research focuses upon the role of cytochrome b in electron transport and energy transduction. The specific aims include: 1) To construct a molecular map of the inhibitor binding domain(s) of the protonmotive cytochrome b of Complex III. 2) To define the role of the cytochrome b inhibitor binding domain(s) in the structure and function of the two redox reaction centers. Particular emphasis will be placed upon testing and refining current models of cytochrome b electron transport. 3) To develop a system of mammalian mitochondrial DNA mutagenesis. 4) To determine the molecular basis of the mitochondrial CAP-R phenotypes and define - at the biochemical level - their effects on mitochondrial protein synthesis and organelle biogenesis. 5) To develop procedures for the direct base sequencing of mammalian mitochondrial DNA or RNA.